Prednisone, azathioprine, and N-acetylcysteine for pulmonary fibrosis

Abstract

Background: A combination of prednisone, azathioprine, and N-acetylcysteine (NAC) has been widely used as a treatment for idiopathic pulmonary fibrosis. The safety and efficacy of this three-drug regimen is unknown.

Methods: In this randomized, double-blind, placebo-controlled trial, we assigned patients with idiopathic pulmonary fibrosis who had mild-to-moderate lung-function impairment to one of three groups -- receiving a combination of prednisone, azathioprine, and NAC (combination therapy), NAC alone, or placebo -- in a 1:1:1 ratio. The primary outcome was the change in longitudinal measurements of forced vital capacity during a 60-week treatment period.

Results: When approximately 50% of data had been collected (with 77 patients in the combination-therapy group and 78 in the placebo group), a planned interim analysis revealed that patients in the combination-therapy group, as compared with the placebo group, had an increased rate of death (8 vs. 1, P=0.01) and hospitalization (23 vs. 7, P<0.001). These observations, coupled with no evidence of physiological or clinical benefit for combination therapy, prompted the independent data and safety monitoring board to recommend termination of the combination-therapy group at a mean follow-up of 32 weeks. Data from the ongoing comparison of the NAC-only group and the placebo group are not reported here.

Conclusions: Increased risks of death and hospitalization were observed in patients with idiopathic pulmonary fibrosis who were treated with a combination of prednisone, azathioprine, and NAC, as compared with placebo. These findings provide evidence against the use of this combination in such patients. (Funded by the National Heart, Lung, and Blood Institute and the Cowlin Family Fund; ClinicalTrials.gov number, NCT00650091.).

Figure 1. Enrollment and Outcomes

DLCO denotes carbon monoxide diffusing capacity, FVC forced vital capacity, IPF idiopathic pulmonary fibrosis, and NAC N-acetylcysteine.

Figure 2. Kaplan–Meier Curves for the Time until Death, Disease Progression, or Hospitalization

Shown are the time until death (Panel A), until a composite of death or disease progression (defined as a decrease in the forced vital capacity of ≥10%) (Panel B), or until a composite of death or hospitalization (Panel C). Combination therapy refers to a three-drug regimen consisting of prednisone, azathioprine, and N-acetylcysteine.

Figure 3. Timeline until Death during the 60-Week Study Period, According to Study Group

Shown are follow-up data for patients from randomization until death (from left to right). Each set of bars represents one patient who died, including eight patients receiving combination therapy and one patient receiving matched placebo. For each patient, three bars are plotted (for N-acetylcysteine [NAC], azathioprine, and prednisone), with darker shading indicating the interval in which the drug was administered and lighter shading indicating the interval in which the drug was not administered. The dark vertical lines with a corresponding number indicate the occurrence of a serious adverse event (SAE), as listed.